Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO

Abstract

Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established, we determined that epithelial cells (ECs) also contributes to this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor-inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3-dioxygenase (IDO) via non-canonical nuclear factor-kB activation. Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis, bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice, underexpressed the IDO-dependent T helper 1/regulatory T cell (Th1/Treg) pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs. Further studies with interferon (IFN)-c, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-c/IDO/ Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth. Thus, distinct immune pathways contribute to resistance and tolerance to the fungus, to which the hematopoietic/non-hematopoietic compartments contribute through distinct, yet complementary, roles.

TLR3 essentially promotes protective class I–restricted memory CD8+ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients

“…Activation of IDO via the TLR3/ TRIF pathway confers tolerogenic and Th1-activating potential to lung DCs in murine aspergillosis. 18,19 Consistently, the enzyme was not induced in infection in the lung of Tlr3 Ϫ/Ϫ mice despite being expressed at the basal level (supplemental Figure 5). Therefore, through IDO, TLR3 likely contributes to the promotion of protective tolerance to the fungus in infection and to the down-regulation of Th17 responses, as shown previously with other lung infections.…”

“…Immunoblotting for IDO was performed with rabbit polyclonal IDO-specific Ab on total lung cells. 18 Scanning densitometry was For personal use only. on May 12, 2018. by guest www.bloodjournal.org From done on a Scion Image apparatus.…”

A GpC-Rich Oligonucleotide Acts on Plasmacytoid Dendritic Cells To Promote Immune Suppression

“…Sustained IDO induction depends on noncanonical NF-kB activation (19). Because TRIF-mediated signaling may involve noncanonical NF-kB family members (38,39), we hypothesized that a TLR7/TRIF axis could be at work in IDO induction by GpC-ODN. Our data revealed that GpC-ODN acts as a tolerogenic signal for pDCs, which are also capable of initiating IDOdependent long-term suppression independent of IDO's catalytic function (40).…”

PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis

“…C57BL/6, BALB/c, and Md2 2/2 recipient mice were exposed to a lethal dose of 9 Gy, infused i.v. with T cell-depleted donor cells ($10 3 10 6 ), and infected with Aspergillus conidia a week later (29).…”

“…Dendritic cells (DC), macrophages, and epithelial cells were purified from lungs as described (25,29). Murine CD11b + Gr-1 + PMN were positively selected with magnetic beads (Miltenyi Biotec) from the peritoneal cavity of uninfected WT 8 h after the i.p.…”